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The Binding of Isaac is one of a handful of games where I'm owed an hononary doctorate. There are people who know the game better than I, of course, and many, many better players than I am but I've spent a lot of time playing and thinking about Isaac.
Why? I wrote a review for Retro Magazine about Isaac once where I articulated a lot of the things I love about the game/series, but I'll go over the bullet points here. Isaac presents the greatest variety of play/verb in the most reasonable span of time. A run very rarely takes me more than 40 minutes and, though a lot of games promise this, every single Isaac run is different. Or is likely to be. There are so many items that present meaningful gameplay change and they interact with one another, creating even more combinations. Your verb set changes in Isaac more than any other game I can think of.
This isn't to mention how the game, despite all the poop and dead baby trappings, supports surprisingly literary reads on story and theme. It's really a perfect game for me. One of my all time favorites. So, how did I get good at it?
Playing it a lot, of course, but there are some tips I can share. I want to throw out a quick caveat: I don't know Afterbirth quite as well as I know the previous iterations. So, while I'll be throwing out a few must grab items, I also know know EVERY single mechanical change in the new version. Specifically, there's this whole new Angel Room/Sacrifice Room meta that I'm pretty clueless about. Anyway, here goes!
Damage is King
There are a lot of stats in Isaac and in order of importance, they are- Damage, Tears (aka rate of fire), Speed, Luck, Range, Shot Speed. Notice that I don't mention health. Of course health is necessary to play but it's often, via deals with the devil, the currency you use to buy damage. So, a big part of getting good at Isaac is learning how little health you need so you know how much you can trade away.
Damage lessens your need for most of the other stats. Damage means killing enemies before they can hurt you. Because enemies are dead, you don't need the speed to dodge them. If you have damage, you're less dependant on luck because you're less dependant on drops. Damage damage damage.
So, what do you do with this information? Prioritize damage items. Blow up every tinted rock to look for small rock. Save up money to buy the Champion Belt. If you have a deal with the devil and you're offered the choice of one hp and Dark Matter, take Dark Matter. HP is the most common item in the game. Ride that line.
When you get further along in your Isaac journey, you can ignore this but for now, put out every fire and shoot every poop. It's going to net you pennies, hearts and spirit hearts.
This includes looking for secret rooms, looking for second secret rooms and going into curse rooms. Secret rooms are bounded on 3 sides by other rooms and each side must be accessable and the boss room can't be among those 3. Second secret rooms are bounded by only one side. Curse rooms have spikes on the doors and don't hurt you on the way in if you're flying. Due dilligence will save you runs!
And work towards unlocks! Several items that are unlocked by beating end game bosses with different characters are really powerful. They're worth pursuing!
Don't Fear the Restart
On PC, you can hold R to restart your run. If you start a run and your first item room contains Cursed Eye or Bob's Brain, I think there's no shame in starting over. When you're a bit further along, it might be fun to see if you can salvage those runs but when you're learning, there's no point in setting yourself up to fail through no fault of your own.
Must Take Items
Damage multiplyers! Some items, though they just say "Damage up," some items give you more damage AND multiply your damage. Specifically, I'm thinking of Magic Mushroom and Cricket's Head. These items are relatively common (you can find Magic Mushroom from blowing up mushrooms) and they're each damage up plus a 1.5 multiplyer. This makes a HUGE difference.
Game breaking high damagers! Mom's Knife and Brimstone both change how you attack drastically but they just shred through enemies. Always pick these up. Polyphemus and Proptosis are included here too.
Weird tear effects! 20/20! This makes you fire 2 tears at once with no reduction in rate of fire. Super potent. Death's Touch couples a significant damage up with a bigger hitbox and piercing shots. Cricket's Body gives you space damage.
Awesome defensive items! Holy Mantle protects you from one hit per room and is invaluable. Dark Bum will grab hearts off the floor and turn them into spirit hearts. Trinity Shield will protect you from a LOT of damage from the front.
Never Take Items
Kamikaze, Isaac's Heart, Bob's Brain, Number 2, Curse of the Tower, Starage Attractor. These items WILL hurt you.
This only scratched the very surface of Isaac knowledge. I'll maybe do a couple videos to attach to this but my old videos are probably still useful for general guiding principles. I could talk about this forever, quite honestly, but instead, I think I'm going to sneak in a quick run before bed.